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PROSTATE CANCER
Lindsay Kaster, PharmD
Clinical Oncology Pharmacist
Boise VA Medical Center
Learning Objectives
� Discuss the cancer diagnosis and screening, including
the role of Prostate Specific Antigen (PSA).
� Review the basics of treatment of prostate cancer.
� Explain the benefits and risks of the latest oral therapies for prostate cancer.
Question
� Which of the following has NOT been shown to increase the risk of prostate cancer?A) Male Gender
B) African-American Race
C) 5-alpha-reductase polymorphism (SRD5A2)
D) Benign Prostatic Hyperplasia (BPH)
E) Age
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Background of Prostate Cancer
� Most common (non-dermatologic) cancer among
men
� 2nd leading cause of cancer-related death in men
� Hormone-dependent
Risk Factors for Prostate Ca
� Race/Ethnicity Effects on Risk Factor
� Scandinavian countries & US = highest reported rates
� African American = highest overall incidence & death rates
� Testosterone levels are 15% higher
� More activation of testosterone receptor
� Japan & Asian countries report lowest rates
�May be due to low activity of 5-alpha-reductase
� Converts testosterone to more active dihydrotestosterone (DHT)
� Also have a diet relatively high in phytoestrogens which may be chemoprotectants
Risk Factors for Prostate Ca
� Family history
�Can increase risk 2 – 3x
� Genetic Links
�Lower number of CAG repeats in the androgen receptor � Higher activation of the receptor & thus cancer
�Variant SRD5A2 of the 5-alpha-reductase enzyme � Increases risk of prostate cancer by increasing activity of that enzyme
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Risk Factors for Prostate Ca
� Environmental Factors
� Smoking & Alcohol
� NOT associated!
� UV exposure
�More cases further away from the equator?
�Obesity
� Diet
�May be associated
� Increased fat and/or meat intake
� Supplementation does not decrease risk
� Vitamin E/Selenium (SELECT Trial)
Mythbustin’ in Prostate Cancer
� No link between prostate cancer and:
� BPH
� Can complicate diagnosis
� Sexual activity
� Vasectomy
� Serum testosterone or DHT not always correlated
with Prostate CA
� Indicates Multifactorial Cause
Prevention of Prostate Cancer
� Prostate Cancer Prevention Trial (PCPT)
�Over 18,000 men with PSA <3 ng/dL
� Finasteride 5mg po daily x7 years
� Treatment group:
� 30% reduction in prostate Ca (NNT=41)
� Higher Gleason Score in those that developed cancer
� Unknown survival benefit
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Question
� What class of medications has been recently
suggested to decrease risk of prostate cancer?
A) Calcium-channel Blockers
B) Beta-Blockers
C) Quinolone antibiotics
D) Statins
E) Prostablationers
Prostate Physiology
� Aids in seminal fluid production and control of urination
� Prostate Specific Antigen (PSA)
� Produced by prostate cells
� Role in prostate growth
� Increased in: � Damage to the prostate� Prostatitis� Benign Prostatic Hyperplasia (BPH)
� Ejaculation
Prostate Cancer Detection
� Prostate Specific Antigen (PSA)
� Cut-off is approximately 4ng/ml� Positive Predictive Value = 30%
� Digital Rectal Exam (DRE)
� Detects nodules, induration & asymmetry
� High interrater variability
� Value of the Test� Positive Predictive Value = 5-30%
Brawer et al. 1999 & Meigs et al. 1996
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Screening Controversy
� Observational Studies� PLCO Study
� Showed no mortality benefit in PSA screening� May not have enough power
� ERSPC Study� 20% relative risk reduction in death rate� More variability in screening methods� 1410 screenings & 48 treatments needed to prevent one death in 10 years
� Meta-analyses� 2010 & 2011
� Screening does NOT reduce death, but does increase cancer diagnosis
Screening Controversy
� American Cancer Society
� Age >50
� American Urologic Society
� Ages 55 – 69
� US Preventative Services Task Force
� No routine screening
� March 2014 – “Radical Prostatectomy is better than watchful waiting”
Diagnosing Prostate Cancer
� Biopsy Recommendations
� Highly recommended in PSA >10ng/mL
� Greater than 50% will have positive biopsies
� Recommended in PSA 4-10ng/mL
� About 20% will have positive biopsies
� 20-40% will have cancer despite PSA <4ng/mL
� Transrectal prostate biopsy is the gold standard of diagnosis
� 6-12 samples taken, give 90% detection
Presti et al. 2000
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Prostate Cancer Staging
� Stage I – Stage II
� Confined to prostate
� Stage III
� Extending outside the capsule
� Stage IV
�Metastatic disease
� Lymph nodes � blood stream � bones �liver & lung
Gleason Score
� Reports primary & secondary
� Helps account for inherent heterogeneity of the prostate
� Summate scores to get total Gleason Score
Histologic Grade Meaning
Gx Cannot be assessed
G1 Well differentiated (Gleason 2-4)
G2 Mod differentiated (Gleason 5-6)
G3-4 Poorly or Undiff (Gleason 7-10)
Treatment Goals
� Overall goal is to minimize overall morbidity &
mortality
� Stage I – III (Stage A – C)
� Active surveillance is appropriate tx
� <10% death over 20 years from low-risk, low-grade tumors
�Goal = Symptom Relief (low risk) vs Cure (high risk)
� Stage IV (Stage D)
� Not curable
�Goal = symptom relief, extend life
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Prostate Cancer Treatment, Stage I - III
� Surgery
� Radical Prostatectomy� 85% cure rate
� Impotence 37%, Incontinence 17%, Mortality 0.3%
� Radiation Therapy� Brachytherapy
� Insertion of radioactive beads into prostate
� Fast, outpatient procedure
� External Beam Radiation Therapy (EBRT)� 7 – 8 weeks of treatment
� 50% incontinence, 30% ED
� Combined with hormones in high risk patients
Prostate Cancer Treatment, Stage IV
� Goal: Shut off
testosterone
� Bilateral orchiectomy
vs
�Medical castration
� LHRH Agonists
� Non-steroidal Antiandrogens
LHRH Agonists
� Leuprolide Depot (Lupron®)
� 7.5mg IM QMonth
� 22.5mg IM Q3Months
� 30mg IM Q4Months
� Leuprolide Suspension (Eligard®)
� 7.5mg SQ QMonth
� 22.5mg SQ Q3Months
� 30mg SQ Q4Months
� 45mg SQ Q6Months
� Goserelin implant (Zoladex®)
� 3.6mg SQ qmonth
� 10.8mg SQ q3months
� Given in upper
abdominal wall
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LHRH Agonists
� Reversible method of androgen ablation as effective as orchiectomy
� Agents:
� Leuprolide
�Goserelin
� Response rate of up to 80%
� AE: disease flare at first week of therapy (bone pain or LUTS) that usually resolves after 2 weeks
LHRH Flare
� Can be fatal in patients with extensive mets
� Antiandrogens used for prevention
� NCCN guidelines recommend use in those patients who are at risk of metastatic symptomatic flare
� Antiandrogens should be used for at least two weeks surrounding LHRH Dose
Non-steroidal Antiandrogens
� Monotherapy shown to be less effective than LH-RH alone
� Response rate 50-87% reported
� Objective responses seen as decreased bone pain, decreased prostate size, decreased PSA and/or improved functional status
� Agents:
� Bicalutamide
� Flutamide
� Nilutamide
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Complete Androgen Blockade
� Combination of Antiandrogen & LHRH agonist
�Good for creating a state of maximal androgen deprivation to avoid other mechanisms of hormonal stimulation of the prostate
� Response rate >90% in untreated patients (<35% in previous tx)
� Improved survival, but may have more AE
Efficacy of ADT
� Early vs Deferred Therapy
� 17% decrease in relative risk for prostate cancer specific mortality
� No decrease in overall mortality
� Intermittent ADT
� Shown to be better tolerated
� Insufficient data- need more clinical trials
Loblaw DA, et al. J Clin Oncol. 2007;25:1596-605
Benefits of ADT
Decrease Decrease
In:In:
ControlControl ADTADT P ValueP Value
Cord Cord
CompressionCompression
4.94.9 1.91.9 <0.025<0.025
Ureteral Ureteral
ObstructionObstruction
11.811.8 7.07.0 <0.025<0.025
MetastasesMetastases 11.811.8 7.97.9 <0.05<0.05
Pathologic Pathologic
FractureFracture
7.97.9 2.32.3 NSNS
Advanced Disease
Sharifi N, et al. JAMA. 2005;294:238-44
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Question
� What are the potential adverse effects of
complete androgen blockade?
A) Fatigue
B) Bone Loss
C) Breast Changes
D) Hot Flashes
E) All of the above
Other ADT ADRs
Braga-Basaria M, et al. J Clin Oncol. 2006;24:3979-83
Castrate-Resistant Prostate Cancer (CRPC)
� Criteria:
� Testosterone <30ng/dL
� Prostate cancer growing, spreading despite this
� Treatment Options:
• Docetaxel + Prednisone• Androgen withdrawal – no survival benefit• Ketoconazole + Hydrocortisone – no survival benefit
Prior to 2004
• Docetaxel + Prednisone• Abiraterone + Prednisone• Sipuleucel-T
Today
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Docetaxel
� Classical chemotherapeutic agent
� 75mg/m2 given every 21 days
� Significant ADRs
� Full-body hair loss
� Neuropathy
� Hypersensitivity Reaction
�Manifests acutely during treatment
� 2/2 Diluent
Abiraterone (Zytiga)
� CYP 17 Inhibitor (17
alpha-hydroxylase)
� Blocks formation of testosterone within tumor cells
� Oral agent
� 4 tabs (1000mg) q day
� Used in combination with
prednisone 5mg po bid
� 4 month survival benefit vs placebo
Abiraterone ADRs
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Sipuleucel-T
� Autologous cells fused with PA2024 gene
� (PAP linked to GMCSF)
� 4 month increase in median survival (vs active controls)
� ADR: COST!, Rigors, tremors, fever, cold sensation
Post-Docetaxel Treatment
� Enzalutamide (Xtandi)
� Small molecule inhibiting overexpression of androgen receptor
� Blocks translocation of the receptor to cell surface
� Binds DNA
� Oral agent
� 4 tabs q day (160mg)
� 5 month survival benefit (vs placebo)
Goodin S. The Oncology Pharmacist. 2009;2(3):10-3
Bone Health in Prostate Cancer
� Preventative
� Androgen Deprivation Therapy
� Annual BMD loss of ~5%/year
�Greatest loss in the first year
�Other risk factors: white, BMI <25, length of ADT
� Treatment:
� Calcium + Vitamin D
� Exercise
� Smoking Cessation
� IV or PO bisphosphonates
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Bone Health in Prostate Cancer
� Palliative
�Metastatic/Lytic bone disease common in CRPC
� Treatment
� Zoledronic Acid 4mg q3 – 4 weeks
� Denosumab 120mg SQ q4 weeks
� Pamidronate and PO bisphosphonates NOT shown to have benefit in this population
� Except clodronate, not FDA approved
Investigational Therapies
� Prostate Cancer Vaccines
� Cabozantinib
Conclusions
� PSA Screening no longer recommended for all
� Hormonal Therapies:
� LHRH Agonists
� Antiandrogens
� Medications for CRPC:
� Abiraterone
� Enzalutamide
� Docetaxel
� Coming Soon:
� Vaccines??!!